DK156477B - METHOD OF ANALOGY FOR THE PREPARATION OF HETEROCYCLIC SUBSTITUTED TETRAHYDRO-THIOPYRANE OR -THIOPHENE-CARBOTHIO-AMID DERIVATIVES - Google Patents

Abstract

Thioformamide derivatives of the formula: <IMAGE> wherein R is hydrogen or alkyl (1 to 4 C), Het is pyridin-3-yl[optionally substituted by alkyl (1 to 4 C) or a halogen], quinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, thiazol-5-yl, thieno[2,3-b]pyridin-5-yl or thieno[3,2-b]pyridin-6-yl, and Y is a valency bond or a methylene radical, are new compounds, which are particularly useful as antihypertensive agents.

Description

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The present invention relates to an analogous process for the preparation of novel heterocyclic substituted tetrahydro-thiopyran or thiophene carbiothioamide derivatives of the general formula 5 Y YV CSNHR (I) a hydrogen atom or a straight or branched alkyl group having 1 to 4 (preferably 1 or 2) carbon atoms, Het means 3-pyridyl or 3-quinolyl, and Y is a valence bond or methylene group.

The presence of an oxygen atom on the sulfur creates in the molecule an asymmetry which, in combination with the present asymmetric carbon atom, produces four stereoisomers, which may be separated into two racemic pairs, hereinafter referred to as "form A" or "the most po - learn product "and" form B "or" the least polar product ". Polarity is determined by thin layer chromatography. These forms can themselves be divided into isomers. The present invention comprises the preparation of all the stereoisomeric forms and mixtures thereof.

The process of the invention for the preparation of the compounds of the general formula (1) is characterized in that ammonia or an amine of the general formula R - NH 2 (II) 30 wherein R is as defined above is reacted with a dithioester of the general formula v CSSR * - - if you) -s / ^ Het 35 0 wherein the symbols Het and Y have the meanings given above.

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and R 'means a straight or branched alkyl group having 1-4 carbon atoms, a benzyl group or a carboxymethyl group upon which the resulting product is isolated and the stereoisomeric forms, if desired, separated.

The reaction is usually carried out with an excess of the amine of formula (II) either without the use of solvents or in an organic solvent such as an aromatic hydrocarbon, ether or low molecular weight alcohol or a mixture of these solvents, at a temperature. between 20 and 130 ° C and optionally under pressure.

It is particularly convenient to bind the thiol formed during the reaction as a heavy metal salt using a thiol acceptor such as mercury (II) chloride.

Separation of forms A and B may be effected by subjecting the resulting mixture to crystallization or chromatography.

The dithioester sulfoxides of general formula (III) 20 can be prepared as set forth below.

(1) By reacting a strong base with a compound of the general formula / - Y \ 25 ^ CH - Het (IV)

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wherein Het and Y have the above meanings, wherein the resulting compound is first reacted with carbon disulfide and then with a compound of the general formula R '- Z (V) wherein R * has the meaning given above and Z represents a halogen atom, preferably a chlorine atom, a bromine atom or 35 Ο

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an iodine atom, or a reactive ester group, preferably a mesyloxy group or a tosyloxy group.

The reaction is usually carried out in an ether such as tetrahydrofuran, to which is usually added hexamethylphosphoramide. The reaction temperature is between -20 ° C and + 50 ° C.

As a strong base, it is particularly convenient to use potassium tert, butylate.

The compounds thus obtained of the general formula (III) exist as a mixture of sulfoxides of different stereochemical form, whereby the relative ratios of these forms vary depending on the nature of the symbol Y. When Y represents a valence bond, the sulfoxides of formula (III) exist ) mainly in a form which, upon treatment with amines of formula (II), gives a thioamide of formula (I) in form B (the least polar form). When Y is a methylene group, the sulfoxides of formula (III) exist mainly in a form which, upon treatment with amines of formula (II), gives a thioamide of the general formula (I) in form A 20 (the most polar form) .

The compounds of general formula (IV) can be prepared according to one of the methods set forth below.

(a) By cyclizing a compound of the general formula Het - CHO S (CHO) X (VI) 6 ψ / o o wherein Het has the meaning given above, m means 3 or 4, and X means a halogen atom, preferably a chlorine or bromine atom, or a reactive ester group, preferably a mesyloxy or tosyloxy group.

The reaction is usually carried out in an anhydrous organic solvent, such as tetrahydrofuran or hexamethylphosphoramide or a mixture of these solvents, at a temperature between -20 ° C and + 50 ° C and in the presence of an organic base such as potassium tert.butylate. .

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In practice, it is possible to prepare dithioesters of the general formula (III) by starting from the compound of the general formula (VI) without isolating the compound of the general formula. (IV). In this case, the compound of formula (VI) is cyclized under the above conditions, in which case at least two equivalents of potassium tert.butylate are used, to which carbon disulfide and the compound of formula (V) are added and proceed as described above.

The compounds of the general formula (VI) can be prepared by oxidation of a sulfide of the general formula

Het - CH 2 S (CH 2) mX (VII) wherein Het is as defined above, m means 3 or 4, and X is a halogen atom, preferably a chlorine or bromine atom, or a reactive ester group, preferably a mesyloxy. or tosyloxy group.

The oxidation is provided by using an equivalent of an agent which is generally used to transfer a sulfide into a sulfoxide, the oxidation being carried out in a suitable solvent. There 25, e.g. hydrogen peroxide is used in acetone or in acetic acid, an alkali metal periodate in an aqueous organic solvent such as water ethanol or water - acetonitrile, or a peroxycarboxylic acid (peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, p-nitroperbenzoic acid) dichloromethane, dichloroethane), in acetic acid or in a mixture of these solvents. The reaction is usually carried out at a temperature between -10 ° C and + 30 ° C.

In practice, it is particularly convenient to use 35 m-chloroperbenzoic acid and carry out the oxidation in methylene chloride at a temperature in the vicinity of 20 ° C.

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The sulphides of general formula (VII) can be prepared as described in European patent application published under number 0046.417.

(b) Upon oxidation of a compound of the general formula / - "- <CE-Het (VIII) \ _s / 10 wherein Y and Het have the meanings set forth above.

The oxidation is provided under the above conditions for the preparation of the compounds of general formula (VI).

The compounds of general formula (VIII) can be prepared as described in European patent application published under the number 0046.417.

(2) Weight oxidation of a dithioester of the general formula -Yv CSSR1 X (IX> _S ^ Het wherein the symbols Het, Y and R 'have the meanings set forth above.

The oxidation of the compounds of general formula (IX) can be provided under the conditions set out above for the preparation of the compounds of general formula (VI).

The compounds of general formula (III) prepared according to process (2) exist as a mixture of diastereomeric sulfoxides, the relative ratios of which vary between 50:50 and 75:25 depending on the nature of the symbols Y, R 'and Het.

The compounds of general formula (III) prepared according to the above methods (1) and (2) 35 can be used to prepare compounds of general formula (I), whereby the compounds of formula (III)

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is used either directly in the form of a diandereomeric forms or used after separation of these forms. The separation of the diastereomeric forms of these compounds can be obtained by fractional crystallization or preferably by chromatography.

The dithioesters of the general formula (IX) can be prepared according to the method described in European patent application published under number 0046.417.

The present compounds of formula (I) can be purified by conventional physical methods, especially crystallization and chromatography.

European patent application published under the number 0046417 describes the sulfides which correspond to the compounds of formula (I). These sulfides are effective as antihypertensive agents.

The compounds of formula (I) disclosed herein exhibit improved antihypertensive properties relative to the aforementioned corresponding sulfides, which could not be predicted.

At oral doses between 0.02 and 50 mg / kg, the 20 compounds decrease arterial pressure in spontaneously hypertensive rats (SHR rats) of the Okamoto-Aoki strain. The use of spontaneously hypertensive rats to study compounds with antihypertensive effect is described by J.L. Roba. Lab. Anim. Sci., 2_6, 305 (1976).

When administered orally to mice, the lethal dose (DLj-q) of the compounds is usually greater than 300 mg / kg.

As stated above, the presence of an oxygen atom on the sulfur atom causes an asymmetry in the molecule, and this asymmetry, combined with the tallying asymmetric carbon atom, produces four stereoisomers which form two racemic pairs designated "form A" or "the most polar product" and "form, respectively. B "or" the least polar product ".

The compounds of general formula (I) present in the most polar form are of particular interest:

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Among the compounds of general formula (I) present in the most polar form are those compounds of particular interest wherein the symbol R represents an alkyl group having 1 to 3 carbon atoms, Het means a 3-pyridyl group 5 or a 3-quinolyl group , and Y represents a methylene group.

Most interesting are those compounds wherein the symbol R represents a methyl group or an ethyl group, Het represents a 3-pyridyl group or a 3-quinolyl group, and Y represents a methylene group.

The following compounds are particularly interesting: N-methyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbothioamide-1-oxide, form A (the most polar product), N-ethyl-2- (3-pyridyl) tetrahydrothiopyran 2-carbothioamide - 1-oxide, form A (the most polar product), N-methyl-2- (3-quinolyl) tetrahydrothiopyran-2-carbothioamide - 1-oxide, form A (the most polar product) , N-methyl-2- (3-pyridyl) tetrahydrothiophene-2-carbothioamide - 1-oxide, form A (the most polar product).

The process of the invention is elucidated in more detail by the following examples.

Example 1

To a solution of 10.2 g of methyl 2- (3-pyridyl) -tetrahydrothiopyran-2-carbodithioate-1-oxide (only a stereoisomeric form) in 150 cm of ethanol, the solution is kept at a temperature of between 25 and 30 ° C, 3 drops are added in the course of 5 rains 10.2 cm of a solution of methylamine in ethanol (33 g per 100 ml). The solution is then stirred for 1 hour and 35 minutes at a temperature in the neighborhood of 30 ° C, after which an additional 1.5 cc of the solution of methylamine in ethanol (33 g per 100 ml) is added.

After stirring for 1 hour at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (25 mm Hg, 3.4 kP.a) at 40 ° C. The resulting product (35.8 g) is dissolved in 15 cm of acetonitrile at a temperature of approx. 20 ° C and the resulting solution is kept for 1 hour 8

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o at a temperature of approx. 5 ° C. The crystals formed are separated by filtration, washed twice with a total of 10 cm of acetonitrile and dried under reduced pressure (25 mm Hg, 3.4 kPa) at 20 ° C. To the resulting product (3.4 g) was added 5 0.8 g of product prepared under the same conditions and the 3 product mixture dissolved in 80 cm of boiling acetonitrile.

To the solution is added 0.1 g of decolorizing coal, after which the solution is filtered in heat and the filtrate is cooled for 10bet of two hours at a temperature of approx. 5¾. The formed 10 crystals are separated by filtration, washed twice with 3 total 10 cm of acetonitrile and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 60 ° C. There was thus obtained 3.3 g of N-methyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbothioaraide-1-oxide (form A), mp 228 ° C. The product gives a 15 Rf value of 0.22 by thin layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio 80:20 as solvent.

Methyl 2- (3-pyridyl) tetrahydrothiopyran-2-carbodi-thioate-1-oxide (only a stereoisomeric form) can be prepared as follows.

A solution of 16.7 g of 3 - [(4-chlorobutyl) sulfinyl-3-methyl] pyridine in 90 cm of anhydrous tetrahydrofuran is added dropwise for 10 minutes in 20 minutes, keeping the temperature below 12 ° C, to a solution of 16.2 g potassium tert.butylate 25 in a mixture of 90 cirr anhydrous:. tetrahydrofuran and 19 cnr anhydrous hexamethylphosphoramide. After stirring for 30 minutes at a temperature of approx. 10 ° C is added dropwise over 5 minutes and at the same temperature a solution 3 of 16.5 g of carbon disulfide in 15 cm of anhydrous tetrahydrofuran.

Stir for 10 minutes, then add a solution of 30.8 g of methyl iodide in 15 cm of anhydrous tetrahydrofuran. The reaction mixture is then stirred for 30 minutes, allowing the temperature to gradually rise to 20 ° C. After 3 addition of 500 cm distilled water, 35 3 are extracted four times with a total of 450 cm ethyl acetate. The organic extracts are combined, washed four times with a total of 600 cm distilled water, dried over anhydrous sodium sulfate and 0 9

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concentrated to dryness under reduced pressure (25 mm Hg, 3.4 kPa) at 40 ° C. The resulting product (12.6 g) is chromatographed on 130 g of neutral silica gel in a column of 3.7 cm diameter. It is eluted with mixtures of cyclohexane and ethyl acetate with increasing ethyl acetate content to remove the ethyl acetate. compounds which are less polar than the desired product (Rf = 0.39 by thin layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the 80:20 volume as solvent). Then elute 10 with pure ethyl acetate and collect 14 fractions 3 with a volume of 300 cm. These fractions are combined and concentrated to dryness under reduced pressure (25 mm Hg, 3.4 kPa) at 40 ° C. There is thus obtained 4.4 g of methyl 2- (3-pyridyl) tetrahydrothiopyran-2-carbodithioate-1-oxide (only a stereoisomeric form) having a melting point of 150 ° C.

3 - [(4-Chlorobutyl) sulfinylmethyl] pyridine can be prepared as follows.

To a solution of 103 g of (4-chlorobutyl) (3-pyridyl-3-methyl) sufide in 900 cm of methylene chloride is added dropwise over a period of 1 hour and 30 minutes and at a temperature of approx. 20 DEG C. a solution of 107 g of 85% m-chloroperbenzoic acid 3 in 900 cm of methylene chloride. After stirring for 17 hours at the same temperature, 3 liters of a water solution containing 10% by weight sodium bicarbonate is slowly added. The organic solution is decanted and then washed with 1 liter of 10% sodium bicarbonate solution. The aqueous phases are combined 3 and extracted with 500 cm of methylene chloride. The organic extracts are combined and washed twice with a total of 2 liters of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (25 mm Hg, 3.4 kPa) at 35 ° C. The resulting product (87 g) is chromatographed on 400 g of neutral silica gel in a column of 4.7 cm diameter. Elute with 10 liters of methylene chloride and collect three fractions with a volume of 1 liter, ten fractions of 35 cm with a volume of 100 cm and twelve fractions with a volume of 3,500 cm. Fractions 11-25 are combined and concentrated to 0

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dryness under reduced pressure (25 mm Hg, 3.4 kPa) at 35 ° C. There is thus obtained 25.4 g of 3 - [(4-chlorobutyl) sulfinylmethyl] pyridine in the form of an orange oil.

The product gives an Rf value of 0.22 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

Example 2 For a solution of 10.7 g of methyl 2- (3-pyridyl) -3 tetrahydrothiopyran-2-carbodithioate-1-oxide in 120 cm of ethanol, the solution is maintained at a temperature of between 20 and 25 ° C. 34 g of ethylamine are added dropwise over the course of 5 minutes. The solution is then stirred for 1 hour and 30 minutes at the same temperature, whereupon it is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 50 ° C. The resulting product (12 g) is chromatographed on 145 g of neutral silica gel (0.040-0.063 mm) in a column with a diameter of 4 cm under a pressure of 40 kPa. The column is eluted with a mixture of 20 ethyl acetate and methanol in the ratio of 90:10, and 3 a fraction with a volume of 300 cm and 32 fractions with a volume of 120 cm are collected. Fractions 16-33 are combined and concentrated to dryness under reduced pressure o (20 mm Hg, 2.7 kPa) at 40 C. The resulting product 25 (4g) is dissolved in a boiling mixture of 9 cm methyl ethyl 3 ketone and 2 cm ether. After cooling, the solution is kept at a temperature of approx. 0 ° C for 2 hours. The crystals formed are separated by filtration, washed with 3 3 3 cm of methyl ethyl ketone and with 0.5 cm of isopropyl ether and dried under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of approx. 20 ° C. To the resulting product (2.6 g) is added 1.2 g of product prepared under the same conditions in a previous experiment and the product mixture is dissolved in 3 25 cm of boiling methyl ethyl ketone. The resulting solution 35 is added with 0.2 g of decolorizing coal and filtered in heat.

The filtrate is cooled and kept for 1 hour and 30 minutes at a temperature of approx. 0 ° C. The crystals formed are separated from 0 11

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3 by filtration, wash with 6 cm of methyl ethyl ketone and terres under reduced pressure (1 mm Hg, 0.13 kPa) at 60 ° C. There are thus obtained 3 g of N-ethyl-2- (3-pyridyl) tetrahydro-thiopyran-2-carbothioamide-1-oxide (Form A), which first melts at 169 ° C, then strengthens pany and then melts at 183 ° C. The product gives an Rf value of 0.30 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

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Example 3

Proceed in the same manner as described in Example 2, but proceed from propylamine. There is thus obtained N-propyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbothioamide-1-oxide having a melting point of 184 ° C. The product gives an Rf value of 0.34 by thin layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

Example 4

Proceed in the same manner as described in Example 2, but proceed from isopropylamine. There is thus obtained N-iso-propyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbothioamide-1-oxide having a melting point of 209 ° C. The product gives a 25 Rf value of 0.36 by thin layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

EXAMPLE 5 A solution of 7.7 g of methyl 2- (3-quinolyl) tetra-3-hydrothiopyran-2-carbodithioate-1-oxide in 160 cm of ethanol is kept at a temperature close to 20 °. C, 55 cm 3 of a solution of methylamine in ethanol (33 g per 100 ml) is added dropwise in 10 minutes of 25 minutes.

The solution is then stirred for 15 hours at the same temperature.

The crystals formed are separated by filtration, washed

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0 3 3 with 10 cm of ethanol and then three times with a total of 45 cm of isopropyl ether and dried under reduced pressure (0.2 mm Hg, 0.027 kPa) at 50 ° C. To the resulting product (3.8 g), 0.95 g of product prepared under the same conditions is added in a previous experiment and the product mixture is dissolved 3 in 600 cm of boiling methanol. The solution is added to 4 g of decolorizing coal and filtered in heat. The filtrate is cooled and kept at a temperature near 5 ° C for 15 hours.

The solid formed is separated by filtration, washed four times with a total of 80 cm 3 of nethanol and dried under reduced pressure (0.2 mm Hg, (0.027 kPa) at a temperature in the vicinity of 60 ° C). 3 g of N-methyl-2- (3-quinolyl) tetrahydrothiopyran-2-carbothioamide-1-oxide having a melting point of 280 ° C. The product gives an Rf of 0.38 by thin layer chromatography on silica gel under using a mixture of ethyl acetate and methanol in the 80:20 volume ratio as a solvent.

Methyl 2- (3-quinolyl) tetrahydrothiopyran-2-carbodithioate-1-oxide can be prepared as follows.

A suspension of 34.5 g of 2- (3-quinolyl) tetrahydrothiopyran-1-oxide in 280 cm of anhydrous tetrahydrofuran is added dropwise over 10 minutes for 45 minutes and at a temperature in the vicinity of 20 ° C to a solution of 34. 9 g of potassium tert.butylate in 800 cm 2 of anhydrous tetrahydrofuran. The mixture is then stirred for 1 hour at the same temperature. A solution of 27 g of carbon disulfide 3 in 60 cm of anhydrous tetrahydrofuran is then added dropwise over a period of 15 minutes at a temperature of -4 ° C. After 30 minutes of stirring, a solution of 51 g of methyl iodide in 60 cm of anhydrous tetrahydrofuran is added dropwise over 15 minutes at the same temperature. The mixture is then stirred for 30 minutes, gradually raising the temperature to 12 ° C. The solid formed is separated by filtration, washed with methylene chloride (200 cm) and discarded. The filtrate and washings are combined and concentrated to dryness under reduced pressure (25 mm Hg, 3.4 kPa) at 45 ° C. The resulting product (51 g) is dissolved in 0 3 13

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250 cm methylene chloride. The resulting solution is washed 3 with 150 cm distilled water, dried over anhydrous magnesium sulfate and poured onto 770 g of neutral silica gel (0.063-0.200 mm) in a 7 cm diameter column. The column is eluted with 5 13 liters of a mixture of methylene chloride and ethyl acetate in the 50:50 volume ratio, thereby collecting fractions of 1000 cm volume. Fractions 9-13 are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. There is thus obtained 7.85 g of methyl 2- (3-10-quinolyl) tetrahydrothiopyran-2-carbodithioate-1-oxide having a melting point of 210 ° C. The product gives an Rf value of 0.39 by thin layer chromatography on silica gel using ethyl acetate as solvent.

2- (3-Quinolyl) tetrahydrothiopyran-1-oxide can be prepared as follows.

A solution of 58.4 g of 3 - [(4-chlorobutyl) sulfinylmethyl] -3 quinoline in 450 cm of anhydrous tetrahydrofuran is added dropwise in 10bet of 1 hour and 15 minutes at a temperature near 0 ° C to a solution of 44 8 g of potassium tert-butylate in 3,200 cm of anhydrous tetrahydrofuran. The mixture is stirred for 16 hours, allowing the temperature to rise to 18 ° C.

For a period of 15 minutes and at a temperature of between 2 and 10 ° C, dropwise 15 cc of acetic acid is added thereto.

The solid formed is separated by filtration, washed twice with a total of 360 cm of methylene chloride and discarded. The filtrate and washing solutions are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 45 ° C. The resulting product (51 g) is chromatographed on 185 g of neutral silica gel (0.063-0.200 mm) in a column of 6.8 cm diameter. The column is eluted with 200 cm 2 of methylene chloride, then with 2200 cm 2 of ethyl acetate and finally with 3 1600 cm of a mixture of ethyl acetate and methanol in the ratio of 90:10. 40 fractions with 3 volumes of 100 cm are collected. Fractions 25-40 are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at

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Ο 14 45 ° C. There is thus obtained 35.8 g of a mixture of two forms of 2- (3-quinolyl) tetrahydrothiopyran-1-oxide having a melting point of 152-154 ° C.

The product gives an Rf value of 0.09 and 0.17 by 5 thin layer chromatography on silica gel using ethyl acetate as solvent.

3 - [(4-Chlorobutyl) sulfinylmethyl] guinoline can be prepared as follows.

To a solution of 54.8 g of (4-chlorobutyl) (3-quinolyl-3-methyl) sulfide in 1160 cm of methylene chloride is added dropwise over a period of 1 hour and 15 minutes and at a temperature near 20 ° C. of 44.4 g of 82.5% m-chloroperbenzoic acid 3 in 450 cm of methylene chloride. After stirring for 18 hours at the same temperature, 560 cc of aqueous solution of sodium bicarbonate (8 g per 100 ml) is slowly added. The organic solution is decanted, washed with 200 cm 8% aqueous solution 3 of sodium bicarbonate and then twice with a total of 300 cm distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (20 mm Hg, 20 2.7 kPa). ) at 45 ° C. There is thus obtained 58.1 g of 3 - [(4-chlorobutyl) -sulfinylmethyl] quinoline having a melting point of 103 ° C.

(4-Chlorobutyl) (3-quinolylmethyl) sufide can be prepared as follows.

To a solution of 87 g of dihydrochloride of 2- (3-25-quinolylmethyl) isothiourea in 200 cc of distilled water, which solution is kept at a temperature near 0 ° C, 93 cc of a 10 N aqueous solution of sodium hydroxide is added. within 12 minutes. After heating for 20 minutes at a temperature in the vicinity of 70 ° C and 30 minutes cooling to 12 ° C, 3 g of triethylbenzylammonium chloride and 125 cm of methylene chloride are added.

Then, 51.5 g of 1-bromo-4-chlorobutane are added dropwise at a temperature of 4 ° C and stirring is continued for 16 hours at a temperature of 20 ° C. The organic phase is separated by decantation and the aqueous phase is extracted 3 times with about 100 cm of methylene chloride. The organic 15

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0 3 extracts are combined, washed twice with 100 cm distilled water, dried over anhydrous magnesium sulfate and poured onto 230 g of neutral silica gel (0.063-0.200 mm) in a column with a diameter of 4.2 cm. The column is eluted with 35 1380 cm of methylene chloride. First, a fraction 3 with a volume of 220 cm is collected which is discarded.

A fraction of 1160 cm containing 54.8 g of (4-chlorobutyl) (3-quinolylmethyl) sulfide is then collected. The weight is determined by analyzing the solution with 10 perchloric acid. The solution is used at the following synthesis step without isolating the product. The product gives an Rf value of 0.65 by thin layer chromatography on silica gel using ethyl acetate as solvent.

The dihydrochloride of 2- (3-quinolylmethyl) isothiocarbamide can be prepared as described in European patent application published under the number 0046417.

Example 6

To a solution of 0.35 g of methyl 2- (3-pyridyl) -20 tetrahydrothiopyran-2-carbodithioate 1-oxide (the least polar form with an Rf of 0.13 by thin layer chromatography on silica gel using ethyl acetate as a solvent) in 2 cm of ethanol is added dropwise over

A

5 minutes and at a temperature in the neighborhood of 20 ° C 2 cin 25 of a solution of methylamine in ethanol (33 g per 100 ml).

After stirring for 2 hours at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 30 ° C. The resulting product (0.28 g) is chromatographed on 35 g of neutral silica gel 30 (0.040-0, 063 mm) in a column with a diameter of 2 cm under a pressure of 40 kPa. Eluted in the above order 3 with 100 cm 3 of methylene chloride, 100 cm of ethyl acetate and 3 100 cm of a mixture of ethyl acetate and methanol in the ratio of 90:10 and 11 fractions of 35 volumes of 20 cm are collected. Fractions 6-11 are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) 16

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o at 40 ° C. There was thus obtained 0.22 g of crude N-methyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbothioamide-1-oxide (form B, the least polar form).

The product gives an Rf value of 0.48 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

Methyl 2- (3-pyridyl) tetrahydrothiopyran-2-carbo-dithioate-1 oxide can be prepared as follows.

A solution of 1.6 g of methyl 2- (3-pyridyl) tetra-3-hydrothiopyran-2-carbodithioate in 15 cm of methylene chloride is added dropwise for 10bet of 30 minutes at a temperature near 20 ° C. of 1.25 g of 82.5% m-chloroperbenzoic acid in 10 cm of methylene chloride. After stirring for 20 hours at the same temperature, the reaction mixture of 40 µg of neutral silica gel is poured into a column of 2.6 cm diameter.

The column is eluted with in the above order 300 cm of methylene chloride, 400 cm of a mixture of methylene chloride and ethyl acetate in the 50:50 volume ratio and 1 liter of ethyl acetate. First a fraction with a volume 3 3 of 300 cm is collected, then a fraction with a volume of 400 cm and finally 39 fractions with a volume of 25 cm.

Fractions 8 to 28 are combined and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa) at 40 ° C.

There is thus obtained 0.5 g of the least polar form of methyl -2- (3-pyridyl) tetrahydrothiopyran-2-carbodithioate-1-oxide.

The product gives an Rf value of 0.13 by thin-layer chromatography on silica gel using ethyl acetate as solvent.

30 Fractions 30-41 are combined and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa) at 40 ° C. There is thus obtained 1 g of the most polar form of methyl 2- (3-pyridyl) -tetrahydrothiopyran-2-carbodithioate-1-oxide. The product gives an Rf value of 0.07 by thin layer chromatography on silica gel 35 using ethyl acetate as solvent. This product is identical to the dithioester whose preparation DK 156477 B! 170 is described in Example 1.

Methyl 2- (3-pyridyl) tetrahydrothiopyran-2-carbodi-thioate can be freely adjusted as follows.

3

To 47 cm of a 1.6M solution of n-butyl lithium in hexane, which is kept under nitrogen atmosphere and cooled to -61 ° C, a solution of 7/6 g of diisopropylamine is added dropwise over 30 minutes. of a mixture of anhydrous hexamethylphosphoramide and anhydrous tetrahydrofuran in the volume ratio 47:53. Then, over a 10 minute period, a solution of 6.45 g of 3 (4-chlorobutyl) (3-pyridylmethyl) sulfide in 30 cm of a mixture of anhydrous hexamethylphosphoramide and anhydrous tetrahydrofuran in volume 47:53 is added. After stirring for 1 hour at a temperature close to -60 ° C, a solution of 9.1 g of carbon disulfide in 30 cm of a mixture of anhydrous hexamethylphosphoramide and anhydrous tetrahydrofuran in volume 47:53 is added over a period of 3 to 10 minutes. After stirring for 10 minutes at the same temperature, a solution of 17 g of methyl iodide in 30 cm 2 of a mixture of anhydrous hexamethyl phosphoramide and anhydrous tetrahydrofuran in volume 47:53 is added for 10 to 3 of 10 minutes. The reaction mixture is then stirred for 30 minutes at a temperature in the vicinity of -60 ° C, after which the temperature for 10 minutes of 60 minutes is successively allowed to rise to 10 ° C. After addition

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25 of 100 cm distilled water, the reaction mixture is extracted three times with a total of 400 cm ethyl acetate. The organic 3 extracts are combined and washed three times with a total of 300 cm distilled water. After drying over anhydrous sodium sulfate, filtering and concentrating to dryness, 15.9 g of a brown oil is obtained, which is chromatographed on 160 g of neutral silica gel in a column of 3.7 cm diameter. In this order, eluents are eluted with 500 cm of cyclohexane, 400 cm of a mixture of cyclohexane and ethyl acetate in the ratio of 98: 2, 400 cm of a mixture of cyclohexane and

ISLAND

Ethyl acetate in volume ratio 95: 5, 400 cnr of a mixture of cyclohexane and ethyl acetate in volume ratio 92: 8, 3 GB 184 Ο 400 cm of a mixture of cyclohexane and ethyl acetate 3 of volume 90:10 and 1000 cm of a mixture of cyclohexane and ethyl acetate in the volume ratio 88:12. There is a fraction collected with a volume of 500 cm, eight fractions with a volume of 200 cm and 10 fractions with a volume of 3 100 cm. Fractions 12-19 are combined and concentrated to dryness. There is thus obtained 2.1 g of methyl 2- (3-pyridyl) tetrahydro-thiopyran-2-carbodithioate having a melting point of 90 ° C.

Example 7

To a solution of 12.5 g of methyl 2- (3-pyridyl) -3 tetrahydrothiopyran-2-carbodithioate in 120 cm of methylene chloride, a solution of 9 is added dropwise over a period of 10 minutes at 45 ° C. 8 g of 82.5% m-chloro-perbenzoic acid in 130 cm of methylene chloride. After stirring for 21 hours at the same temperature, the reaction mixture is poured onto 375 g of neutral silica gel (0.063-0.200 mm) in a column of 5 cm diameter. The column is eluted with in the above order 3 liters of methylene chloride, 600 cm 2 of ethyl acetate and 2,800 cm 2 of a mixture of ethyl acetate and methanol in a volume ratio of 80:20. A fraction with a volume of 1 liter and seven fractions with a volume of 200 cm are collected. Fractions 5-8 are combined and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa) at 40 ° C. There was thus obtained 12.5 g of a mixture of two forms of. methyl 2- (3-pyridyl) tetrahydrothiopyran-2-carbodithioate 1-oxide. To a solution of 6 g of this mixture in 50 cm of ethanol is added dropwise in 10bet of 35 minutes at a temperature in the neighborhood of 20 ° C 35 cm 2 of a solution of methylamine. ethanol 30 (33 g per 100 ml). After stirring for 4 hours at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 45 ° C.

There is thus obtained 6.2 g of a crude product which, by thin layer chromatography on silica gel, gives 2 spots with the 35 Rf values 0.48 and 0.22 (mixture of ethyl acetate and methanol in the volume ratio 80:20 as eluent).

Ο DK.156477 #.

19

The two products corresponding to these spots can be separated as follows.

3

The crude products are dissolved in 55 cm methylene chloride and the resulting solution is poured onto 100 g of neutral silica gel (0.040-5 0.063 mm) in a column of 2.6 cm diameter, the column is eluted under pressure of 40 kPa with 480 cm ethyl acetate, 3 whereby six fractions of 80 cm volume are collected. Fractions 4-6 are combined and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa) at 40 ° C. To the resulting product (1.1 g) is added 1.7 g of the same product prepared under the same conditions in a previous experiment.

3

The product mixture is dissolved in 25 cm of methylene chloride. The resulting solution is added 0.5 g of decolorizing coal and 3 filtered. The filtrate is washed three times with a total of 15 cm 3 of methylene chloride. After the addition of 125 cm of cyclohexane, the mixture is kept for 15 hours at a temperature close to 5 ° C.

The crystals formed are separated by filtration, washed three times with a total of 50 cm of cyclohexane and dried under reduced pressure (0.1 mm Hg, 0.13 kPa) at 50 ° C. There is thus obtained 1.90 g of Form B of N-methyl-2- (3-pyridyl) tetrahydrothiopyran-2-carbo-thioamide-1-oxide (the least polar form) having a melting point of 154 ° C. The product gives an Rf value of 0.48 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio 80:20 as solvent.

By continuing the chromatography one can obtain form A (the most polar form) which has a melting point of 228 ° C. This product gives an Rf value of 0.22 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

Example 8

To a solution of 2.7 g of methyl 2- (3-pyridyl) -tetrahydrothiophene-2-carbodithioate-1-oxide (mixture of

DK 156477 B

ISLAND

two stereoisomeric forms) in 25 cm of ethanol are added 3 2.7 g of mercury (II) chloride and 5 cm of distilled water.

For 10 minutes at a temperature close to 15 ° C, 5 cm 3 of a solution of 5 methylamine in ethanol (33 g per 100 ml) is added dropwise. The resulting mixture is stirred for 30 minutes at the same temperature, after which another 3 cm of the solution of methylamine in ethanol is added. After stirring for 30 minutes, the insoluble substance formed is separated by filtration and the filtrate 10 is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. There is thus obtained 5 g of crude product, obtained by thin layer chromatography on silica gel to give two spots with the Rf values of 0.20 and 0.13 (mixture of ethyl acetate and methanol in volume 80:20 as eluent).

15 The products which correspond to these stains can be separated 3 as follows. The crude products are added to 10 cm of methanol. The resulting solution is filtered and poured onto 75 g of neutral silica gel (0.040-0.063 mm) in a column with a diameter of 2.5 cm. Under a pressure of 50 kPa, column 3 is first eluted with 2,040 cm of a mixture of ethyl acetate and methanol 3 in the 95: 5 volume ratio, and then with 960 cm of a mixture of ethyl acetate and methanol in the 90:10 volume ratio. Collect fractions with a volume of 60 cm.

(a) Fractions 19-31 are combined and concentrated to 25 dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. This gives 0.7 g of product, which is purified in the following 3 ways. The product is suspended in 15 cm of boiling acetonitrile and the suspension is filtered in water. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The resulting product (0.4 g) is dissolved in 4 ml of boiling ethanol. After cooling, the solution is kept for 30 minutes at 0 ° C. The crystals formed are separated by filtration, washed 3 times with a total of 1 cm of ethanol and dried under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature in the vicinity of 20 ° C. There is thus obtained 0.15 g of N-methyl-2- (3-pyridyl) -tetra-hydrothiophene-2-carbothioamide-1-oxide (form B) having a melting point of 158 ° C. This product gives an Rf value

DK 156477 B

0.21 to 0.20 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the 80:20 volume as solvent.

(b) Fractions 38-50 are combined and concentrated to 5 dryness under reduced pressure (20 mm Hg, 2.1 kPa). There is thus obtained 0.65 g of product which is purified in the following manner. The product 3 is suspended in 12 cm of boiling acetonitrile and the suspension is filtered in heat. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The resulting product (0.4 g) is dissolved in 2.5 cm of boiling acetonitrile.

After cooling, the solution is kept at 0 ° C for 30 minutes.

The crystals formed are separated by filtration, washed 3 times with 1 cm acetonitrile and dried under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature in the vicinity of 15 ° C. There is thus obtained 0.14 g of N-methyl-2- (3-pyridyl) -tetrahydrothiophene-2-carbothioamide-1-oxide (form A) having a melting point of 204 ° C. This product gives an Rf value of 0.13 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol at a volume of 80:20 as solvent.

Methyl 2- (3-pyridyl) tetrahydrothiophene-2-carbodithioate-1-oxide (mixture of two stereoisomeric forms) can be prepared as follows.

To a solution of 11.2 g of methyl 2- (3-pyridyl) -3 tetrahydrothiophene-2-carbodithioate in 150 cm of methylene chloride is added dropwise in 10bet of 1 hour at a temperature near 20 ° C. , 9 g of 85% m-chloro-per-benzoic acid in 150 cm of methylene chloride. After stirring for 17 hours at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 50 ° C. The residue is chromatographed on 550 g of neutral silica gel (0.040-0.063 mm) in a column with a diameter of 6 cm under a nitrogen gas pressure of 50 kPa.

In the order mentioned, elute with 1.2 liters of ethyl acetate, 1.2 liters of a mixture of ethyl acetate and methanol in the ratio 95: 5 and 3.9 liters of a mixture of 22

DK 156477 B

o Ethyl acetate and methanol in the 90:10 volume ratio, and a fraction with a volume of 2.9 liters and 35 fractions with a volume of 100 cm are collected. Fractions 13-35 are combined and concentrated to dryness under reduced pressure 5 (20 mm Hg, 2.7 kPa) at 50 ° C. There is thus obtained 10.2 g of methyl 2- (3-pyridyl) tetrahydrothiophene-2-carbodithioate-1-oxide in the form of an orange oil which forms a mixture of the two stereoisomeric forms in the ratio 50:50.

These ratios are determined by the NMR spectrum of the proton at the 2-position of the pyridine: ($ 8.85 and 8.77 ppm, J = 2.5 Hz (solvent CDCl ^) · By thin layer chromatography on silica gel under using a mixture of ethyl acetate and methanol in the 80:20 volume ratio gives the product mixture only an Rf value equal to 0.37.

15

Example 9

To a solution of 5.8 g of methyl 2- (3-pyridyl) -tetrahydrothiophene-2-carbodithioate-1-oxide (only a stereoisomeric form) in 35 cm of ethanol, which solution is kept

20 O

at a temperature in the vicinity of 25 ° C, 3 ml of a solution of methylamine in ethanol (33 g per 100 ml) is added dropwise over 16 minutes. After stirring for 1 hour at the same temperature, 3 15 cm of a solution of methylamine in ethanol (33 g / ml) is added dropwise over 10 minutes.

(100 ml). After stirring for 50 minutes, the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The resulting product (7.4 g) is chromatographed on 190 g neutral silica gel (0.040-0.063 mm) in a column of 30 cm diameter. At 50 kPa pressure, the column 30 ° is eluted with the order of 500 cm ethyl acetate, 1360 cm of a mixture of ethyl acetate and methanol in the ratio of 97: 3, 760 cm of a mixture of ethyl acetate 3 and methanol in the ratio 95. : 5 and 1240 cm of a mixture of ethyl acetate and methanol in the volume ratio 35 3 90:10. Five fractions with a volume of 100 cm 3 are collected and 84 fractions with a volume of 40 cm. Fractions 53-89 0

23 DK 156477 B

are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The resulting products are dissolved 3 (1.2 g) in 3.5 cm of boiling ethanol. The forward solution is cooled and kept at 0 ° C for 30 minutes. The 5 crystals thus formed are separated by filtration, 3 washed twice with a total of 1 cm of ethanol and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 60 ° C. There was thus obtained 0.28 g of N-methyl-2- (3-pyridyl) tetrahydrothiophene-2-carbothioamide-1-oxide (form B, the least polar form) having a melting point 10 of 156 ° C. The product gives an Rf value of 0.20 by thin-layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

Methyl 2- (3-pyridyl) tetrahydrothiophene-2-carbodithioate-1-oxide may be prepared in the following manner.

To a solution of 14.8 g of potassium tert-butylate in 3 150 cm of anhydrous tetrahydrofuran is added dropwise over a period of 20 minutes at a temperature near 20 ° C a solution of 18.1 g of 2- (3-pyridyl) tetrahydrothiophene-1-oxide in 150 cm 2 of anhydrous tetrahydrofuran. After stirring for 40 minutes, a solution of 14 cm 3 of carbon disulfide in 100 cm of anhydrous tetrahydrofuran is added dropwise for 10 minutes of 15 minutes at a temperature of -20 ° C. After stirring for 25 minutes, a solution of 1.45 cm of methyl iodide 3 in 100 cm of anhydrous tetrahydrofuran is added dropwise over the course of 10 minutes. The reaction mixture is then stirred for 2 hours and 40 minutes, allowing the temperature to gradually rise to 15 ° C. The insoluble substance formed is separated by filtration and washed twice with a total of 120 cm 3 of anhydrous tetrahydrofuran. The filtrate and washing solutions are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The resulting product (25.8 g) is chromatographed on 500 g of neutral silica gel (0.040-0.063 mm) in a column of 6 cm diameter.

35 Under a pressure of 50 kPa, the column is eluted with 6.6 liters of a mixture of ethyl acetate and methanol in the ratio 93: 7, thereby collecting 14 fractions with a volume 0 24

DK 156477 B

3 3 of 250 cm and 31 fractions with a volume of 100 cm.

Fractions 18-36 are combined and concentrated to dryness under reduced pressure (20 irai Hg, 2.7 kPa) at 40 ° C. There is thus obtained 50 g of methyl 2- (3-pyridyl) tetrahydrothiophene-2-carbodi-thioate-1-oxide. The product gives an Rf value of 0.30 by thin layer chromatography on silica gel using a mixture of ethyl acetate and methanol in the volume ratio of 80:20 as solvent.

2- (3-Pyridyl) tetrahydrothiophene-1-oxide may be prepared in the following manner.

To a solution of 62 g of 2- (3-pyridyl) tetrahydrothiophene in 650 cm of methylene chloride is added dropwise in 10bet of 2 hours and 10 minutes at a temperature near 20 ° C a solution of 76.3 g of 85% m-chloroperbenzoic acid in 3,800 cm 2 of methylene chloride. After stirring for 16 hours at the same temperature, the reaction mixture is concentrated to ca. 1/4 of the original volume under reduced pressure, and the concentrate is poured onto 800 g of neutral silica gel (0.063-0.200 mm) in a column with a diameter of 8 cm. 20 is first eluted with 9 liters of methylene chloride and then with 7 liters of a mixture of methylene chloride and methanol in the ratio of 95: 5 to a crude capture ratio and 16 fractions of 1 liter are collected. Fractions 15 and 16 are combined and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C.

The resulting product (54.3 g) is dissolved in 100 cm 3 of methylene chloride, and the resulting solution is washed 2 times 3 with about 100 cm of a 10% aqueous solution of sodium bicarbonate. After decanting, the wash solutions are extracted three times with 300 ml of methylene chloride three times. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. There is thus obtained 32.8 g of 2- (3-pyridyl) -tetrahydrothiophene-1-oxide as a mixture of two stereoisomeric forms. The product mixture gives the Rf values 35 0.36 and 0.40 by thin layer chromatography on silica gel using a mixture of ethyl acetate, methanol, water and acetic acid in the volume ratio 70: 20: 5: 5 as solvent.

DK 156477ΊΒ 25) 2- (3-Pyridyl) tetrahydrothiophene can be prepared according to the method described in European Patent Application published under number 0046417.

The biological activity of the compounds of formula (I) is apparent from the experimental results set forth below.

Comparison of the activity of the sulfoxides of formula (I) 10 and the corresponding sulfides ___ · ____

Antihypertensive activity

Ex. No. Respondent Toxicity in mice in rats (DA_fl in mg / kg (oxygenating (DL, -no po) po) oxide) known -: _-___, sulfide Sulfoxide Sulfide Sulfoxide Sulfide 1 a 300-900> 900 0.1 0.5 15 2 b 300-900 300-900 0.25 2.5 3 c 300-900> 900 5-10 20-50 4 d 100-300 300-900 approx. 20 inactive at 50 5 e nontoxic nontoxic 0.025 20 at 900 at 900 20 8 f - nontoxic 1-2.5 5 at 9 0 Ô

The known sulfides a to f have the formula

25 yrs — X> JCSNHR

Hot in which the symbols have the following meanings:.

26 Ο

Symbols X Hot R

a CH2 3-pyridyl CH3 b CH2 3-pyridyl C2H5 c CH2 3-pyridyl C3H7 5 d CH2 3-pyridyl in C3 H3e CH2 3-quinolyl CH2 f valence-3-pyridyl CH3 bond 2. Applied Assays a ) Toxicity

The dose of the compound (DL DL q) which, after oral administration to mice, is controlled causes 50% of these animals.

B) Antihypertensive activity in rats

The antihypertensive activity is determined in spontaneously hypertensive waking rats (SHR rats of the strain OKAMOTO-AOKI from IFFA-CREDO).

The measurement of the systolic arterial pressure is performed non-invasively on the tail of the waking animal using a sphygmomanometric method.

The compound tested (in aqueous solution or in suspension in aqueous solution of 10% gum arabic) is administered orally.

Each compound is tested in 2, 3 or 4 doses using 4-8 rats per dose.

The arterial pressure of each of the rats was measured before treatment and then 1, 3 and 6 hours after administration of the compound.

Graphically, the active dose (DA ^g) is determined / resulting in a reduction of the systolic arterial pressure of 30 mm Hg (when the effect is at its peak) relative to the baseline value.

ow

Claims (2)

0 DK 156477 B Patent claims. An analogous process for the preparation of heterocyclic substituted tetrahydro-thiopyran or thiophene carbothioamide derivatives of the general formula 5 y \ xsnhr (I) X_s / alkyl represents 1-4 carbon atoms, Het means 3-pyridyl or 3-quinolyl, and Y represents a valence bond or methylene group, characterized in that ammonia or an amine of the general formula R - NH 2 '= (II) wherein R has the meaning given above is reacted with a dithioester of the general formula 20 -Yv CSS R '/> (III) 0 25 wherein the symbols Y and Het have the meanings set forth above and R 1 represents a straight or branched alkyl group having 1 to 4 carbon atoms, a benzyl group or a carboxymethyl group upon which the resulting product is isolated and the stereoisomeric forms, if desired, separated. 2. A process according to claim 1, characterized in that the ammonia or amine of the general formula is reacted with a dithioester of the general formula 5 y-Y. CSS R 'X_s / ^ Het ^ O 10 wherein the symbols Y, Het and R' have the above meanings, and which are already separated in their diastereomeric forms.